Transgenic animals are characterized by the presence of exogenous or non-native DNA integrated into their genetic information. The animals express or do not express, as the case may be, the genetic characteristic encoded by the foreign DNA.
The hepatic cytochrome P450-dependent monoxygenase system plays a central role in mammalian defence against harmful environmental chemicals; it is also a major determinant of the half-life and pharmacological properties of therapeutic drugs and in certain cases, mediates the activation of drugs, toxins and carcinogens to their ultimate toxic species. Several other functions have been ascribed to hepatic P450s, including control of cholesterol and steroid hormone metabolism and bile acid biosynthesis. However, for certain of these pathways, the exact role of P450s in normal homeostasis is unknown.
There have been major advances in understanding the functions, genetics and regulation of these enzymes and more recently their structures. However, many fundamental questions about the role of these enzymes in normal homeostasis and in the metabolism and activity of drugs and chemical toxins remain to be answered. The size and diversity of the P450 multi-gene family results in great difficulties in dissecting out the function(s) of individual hepatic P450s, particularly as many of these enzymes involved in foreign compound metabolism exhibit overlapping substrate specificities. In order to understand the functions of this enzyme system an approach is required which will allow the simultaneous inactivation of large numbers of cytochrome P450s.
All cytochrome P450s located in the endoplasmic reticulum receive electrons from a single donor, Cytochrome P450 Reductase (CPR; NADPH:ferrihemoprotein reductase, EC 1.6.2.4);
conditional deletion of this protein could therefore inactivate all the P450s located in the endoplasmic reticulum in any particular cell type. It is known from the prior art that P450 expression during development is a vital requirement. In recent studies, although a complete deletion of CPR was achieved it was shown to be embryo lethal (1, 2).
A transgenic non-human animal and/or tissue and/or cells derived therefrom that can be used as a model to study the cytochrome P450-dependent monoxygenase system at a molecular and cellular level and all its associated interactions in drug/toxin metabolism and/or disposition would offer immediate advantages to the art and pharmaceutical, agrochemical, chemical and food industries in general and also permit a further understanding of many biochemical mechanisms.